Disproportionation of Pharmaceutical Salts: pHmax and Phase-Solubility/pH Variance

A multiphasic mass action equilibrium model is used to show that the critical pH in the acid–base disproportionation of a solid salt into its corresponding solid free-base form in aqueous suspensions, widely known as “pH max ”, is incompletely interpreted. It is shown that the traditional thermodynamic model does not predict the invariance of pH and solubility during the salt-to-free-base conversion process in an alkalimetric titration. Rather, the conversion entails a range of pH and solubility values, depending on the amount of added excess salt above that needed to form a saturated solution. A more precise definition is proposed for pH max (pH at the max imum solubility of a eutectic mixture), and three new terms are introduced: pH min (pH at the min imum solubility of the eutectic mixture), pH δ ( d isproportionation invariant pH within the eutectic, i.e ., the equilibrium pH of a spontaneously disproportionating salt slurry), and pH γ ( G ibbs pH at which disproportionation yields equimolar amounts of excess salt and excess free-base solids within the eutectic). Two test compounds with reported multiple salts and the free-base solubility values were selected to illustrate the expanded concepts, the bases W R -122455 and RPR-127963. Also, dibasic calcium phosphate was selected as an ionizable test excipient. The salts are designated in the study as μ-type, when they are thermodynamically stable with respect to spontaneous disproportionation in pure water ( e.g ., W R -122455 salts), and δ-type, when they are predicted to spontaneously disproportionate in pure water ( e.g ., RPR-127963 salts). In an alkalimetric titration, when an acidified suspension of a salt of a basic molecule is titrated with a strong base ( e.g ., NaOH), the passage across the eutectic domain (bounded by pH max and pH min ) is often characterized by (a) minimum in ionic strength either at pH max (μ-type salt) or pH δ (δ-type salt) and (b) maximum buffer capacity at pH γ . When the alkalimetric titration is performed with a large excess of added salt, a wide eutectic domain forms: pH max and pH δ remain invariant, but pH min and pH γ shift substantially in pH. The acid–base mass action model described here can be useful in predicting the stability of salt formulations in mixtures with excipients that can act as pH modifiers.